WO2018014894A1

WO2018014894A1 - Medicament containing modified starch for the treatment of anastomoses

Info

Publication number: WO2018014894A1
Application number: PCT/DE2017/000201
Authority: WO
Inventors: Joachim Laas; Kai-Oliver Mutz; Simon Weigmann
Original assignee: PlantTec Medical GmbH
Priority date: 2016-07-18
Filing date: 2017-07-07
Publication date: 2018-01-25
Also published as: DE102016008533A1; US20190388458A1; US20220133773A1

Abstract

The invention relates to a medicament which a.) contains or even consists of carboxymethylated starch and/or b.) contains or even consists of epichlorohydrin-modified starch for the treatment of anastomoses.

Description

DRUGS CONTAINING MODIFIED STARCH

TREATMENT OF ANASTOMOSES

The invention particularly relates to a pharmaceutical. Moreover, the invention relates to a process for the preparation of a medicament, a use of the indicated medicament, a further use and a process according to the invention.

After resection of gastric and intestinal sections are added to

Maintaining the respective body functions these sections

restored by so-called anastomoses, thus by means of a mechanical connection between two anatomical structures, in particular by means of suturing. With these anastomoses, it is desirable that rapid wound healing and rapid union without

Complications take place, whereby the medicament according to invention with the topical application on such Anastomosebereiche excellent Wundheilungs- and Zusammenwachseffekte of the put together

provides anatomical structures such as intestinal pieces; and this at extremely low risk of infection.

In particular, WO2009 / 091549 A1 discloses a hemostatic material, which is a modified starch having a molecular weight greater than 15,000 daltons. The modified starch is biocompatible and is absorbed after degradation via amylases and carbohydrases. For use, methods are disclosed in which the hemostatic material is applied, for example, as a powder or as a gel on skin and internal tissues and for hemostasis, adhesion prophylaxis and improved tissue repair, for

| Confirmation copy | Wound closure and tissue connection in open, endoscopic, laparoscopic and laryngoscopic surgery and traumatology is used. An application for the treatment of anastomoses is not disclosed.

Quite surprisingly, it has been shown according to the invention that the medicament according to the invention is outstandingly suitable for the treatment of anastomoses.

The medicament according to the invention contains up to consists

carboxymethylated starch and / or contains up to epichlorohydrin-modified starch, since surprisingly these two types of starch for the treatment of anastomoses provide excellent results. This is particularly true for the treatment of anastomoses in and / or the intestine, but also for the treatment of anastomoses of mesenchymal organs such as and in particular bones, tendons, muscles, adipose tissue and connective tissue, connective tissue being understood to mean that between two different tissues and / or organs and links them together; For example, sinews do that

Connective tissue between bone and muscle.

The excellent properties are probably based on the following mechanisms:

Due to the above modified starches becomes an early

Body reaction (early body reaction) associated with the migration of macrophargene, followed by fibroblasts, which are responsible as stabilizing factors for the improved anastomotic healing with improved performance.

In this connection, the medicament according to the invention is also suitable for the treatment of epithelial defects and for the treatment of wounds.

Advantageously, the drug is in gel form, and above In addition, the medicament according to the invention advantageously contains water and / or at least one salt, for example and in particular sodium chloride or potassium chloride. It has been positive in practice

that the starch has a molecular weight of 500,000 daltons to 11,000,000 daltons and / or the starch (ie, the starch particles) has a particle diameter of 30 microns to 100 microns.

In the simplest form of the inventive method for

Preparation of the medicament according to the invention consists in providing the above-mentioned modified starch or in treating it with water and optionally salts to form a gel.

The invention likewise claims the use of the medicament according to the invention for the treatment of the indications indicated above.

In addition, the use of a) carboxymethylated starch and or b) epichlorohydrin-modified starch for the preparation of a

Drug for the treatment of anastomoses, especially when the treatments are those mentioned above.

Finally, a method for the treatment of anastomoses is claimed, in which the medicament according to the invention is used, in particular when it is applied topically.

The addition of the medicament or the invention

carboxymethylated starch or of the epichlorohydrin-modif ^'ierten strength - either as a powder or as a gel - means that a gel is formed and this can then act on the anastomotic site area on site. The presence of the hydrospheres (i.e., the above-mentioned starch particles) is associated with increased invasion of cellular components of early healing, with activated macrophargene being reasonably quick in contact with the surface of the hydrogel particles in that sense to form a scaffold followed by other cellular components of early healing. Although that

Polysaccharide scaffold / matrix degrades within days, an increased number of cellular components remain in the healing area providing improved healing, in particular an increased number of macrophages for macropharocytosis of bacteria, apoptotic cells, necrotic cells, foreign protein cells and polysaccharide surfaces determine is. In addition, it is ascertained an increased number of

Fibroblasts and other cellular components of wound healing. These factors accelerate the presence of early healing cells and the subsequent wound healing processes. These cellular components provide the basis for improving anastomotic healing and, moreover, provide better resistance to increase intraluminal pressure or other mechanical stress in the intestinal area, resulting in a reduced incidence of leaks in intestinal anastomoses.

In histological examinations after one week in one area an improved submesothelial healing can be seen, which is caused by the application of the abovementioned starch gel, ie a form of the medicament according to the invention, the remnants (remaining stock)

Hydrobeads, macrophargene and giant cells, fibroblasts and

show emerging connecting fabric.

The improvement in healing is evoked by the presence of the drug of the invention, which is the early cellular

Healing processes, d. H. the migration of macrophargenes followed by

Fibroblasts, activated. The latter are stabilizing factors for improving anastomotic healing with improved performance, ie better resilience to mechanical stress and a reduced incidence of anastomotic insufficiency. The following characterizations of the starch used are advantageous embodiments.

The starch according to the invention is a cross-linked and carboxymethylated starch which contains amylose in a relatively constant ratio of about 20% by weight of amylose and about 80% by weight of amylopectin. The amylose is rather amorphous, the amylopectin represents the crystalline part of the starch. The modified starch is present as salt-starch glycolate. As a rule, it is the sodium salt of a carboxymethyl ether of starch. The modified starch may contain up to 10% by weight of salt (usually sodium chloride). The pH is between 3 and 7.5. The percentage of salt bound to the modified starch is between 2% and 5% by weight.

The modified starch is as white or almost white, fine, flowable

Powder before. The powder is very hygroscopic and practically insoluble in methylene chloride. It gives a translucent suspension in water. The powder consists of irregularly shaped, oval or pear-shaped particles, 30 to 100 μιτι in size, or rounded 10 to 35μιη. The surface area is typically about 0.2 m ² / g. Occasionally occurring compounds of

Particles consist of two to four particles. The particles have an eccentric hilum and clearly visible concentric grooves. Between crossing Nicol prisms, the particles show a distinct black cross on the

Hilum. Small crystals are visible on the surface of the particles. The particles have significant swelling in contact with water or saline solutions, up to about 30 times their own weight.

The synthesis of the modified starch is usually carried out in two steps, each as a suspension, first the cross-linking, then the

Carboxymethylation. Since the reactions take place in the solid phase, the substitution is inhomogeneous. Exterior areas of strength are stronger of the

Modifications affected as the core areas of starch structures. The

Reactions are affected by diffusion within the starch structure and accessibility to the starch structure. Amorphous regions are readily accessible as crystalline regions that are less heavily modified. Both reactions are nonspecific from a chemical point of view and have (as far as diffusion inhibition or steric inhibition is present) no preferred reaction pattern for the individual hydroxyl groups of a glucose unit. Theoretically, the degree of substitution is 3 (all three OH groups of a glucose unit would be substituted).

In fact, the degree of substitution is likely to be about 0.2 to 0.4, i. In about every 4th glucose unit is an OH group substituted (not

the cross-links are also considered). This degree of substitution results from the values for the bound salt.

At the end of the reactions neutralization with succinic acid,

Phosphoric acid, hydrochloric acid, sulfuric acid or citric acid. The choice of acid has an effect on inorganic and organic

Substances which can be detected as residues in the modified starch.

The molecular weight is typically 500,000 to 11,000,000 daltons. A starch particle consists of about 4.5 x 10 ¹⁰ to 2.3 x 10 ¹² amylose molecules and about 5.6 x 10 ⁷ to 1.3 x 10 ¹⁰ amylopection molecules. The extent of cross-linking is about 25-45%.

Possible starch solutions use as liquid phase water, isotonic saline solution, hypotonic, isotonic or hypertonic saline solution with the following cations: sodium, potassium, ammonium, magnesium, calcium, iron (II), iron (III), aluminum; and the following anions: fluoride, chloride, bromide, iodide, oxide, sulfide, carbonate, sulfate, phosphate, nitrate, chromate, permanganate, hexacyanoferrate (II). Ringer's solution, Ringer's acetate solution and Ringer's lactate solution can also be used as the liquid phase.

The following embodiment explains in a non-limiting way and by way of example the subject invention.

Experiment 1

Effect of improved wound healing in colon anastomoses in the mouse model

To study the effect of wound healing enhancing material on the healing of colon anastomoses by measuring the anastomotic burst pressure in the mouse model

test object:

Wound healing improving material

Surname:

Carboxymethylated starch animals:

Black C57BL / 6 mice supplied by Charles River Laboratories, Research Models and Services, Germany GmbH (Sulzfeld, Germany) Animal certificate: 84-02.04.2014.A127

A total of 23 mice (n = 10 per group plus three (3) animals for control) with a body weight of 24 ± 3 g were used.

Operative method:

23 black C57BL / 6 mice were randomized into four groups; (I) a wound-healing material group with colon anastomosis (n = 10), (II) a wound-healing-improving material control group without colon anastomosis (n = 2), (III) a NaCl (0.9%) Control group with colon anastomosis (n = 10) and (IV) a NaCI (0.9%) control group without colon anastomosis (n = 1).

The mice were anesthetized with carprofen (5 mg / kg body weight) via a subcutaneous injection. After induction of anesthesia, the animals were fixed supine. The coat was shaved off. After disinfection (sterile washing) the abdomen was covered. The abdominal cavity was then opened layer by layer by means of a median laparotomy over 1.5 cm and the intestine was exposed. The cecum was cautiously orchestrated. Then the colon was transsected about 1 cm distal to the cecum. The following attachment of a colon anastomosis was performed with twelve (12) interrupted sutures (Vicryl 8/0) under 16x magnification.

The wound healing enhancing material was immediately applied as a powder. Subsequently, the wound healing enhancing material applied to the colon anastomosis was transformed from powder to gel by 0.9% sterile saline. Instead of the wound healing enhancing material, an equal amount of 0.9% sterile saline was applied in both NaCl (0.9%) control groups.

In the two control groups without colon anastomosis, no colon transsection with subsequent colon anastomosis was performed. The

Wound healing material or 0.9% sterile saline was added immediately after laparotomy to the intact colon about 1 cm distal to the cecum.

After completion of the respective operational measures, the

Abdominal cavity closed by a double-row continuous suture with resorbable suture 4/0. The wound was covered aseptically. The mice were placed back in their cages and raised for seven (7) days. All animals received a subcutaneous injection of Meloxican (1 mg / kg body weight) as pain medication as well as 5 mL isotonic saline subcutaneously to avoid dehydration. For further postoperative analgesia, tramadol (2.5 mg / 100 mL drinking water) was added to the drinking water.

Seven (7) days after surgery, the animals were sacrificed by suffocation with CO 2. There was a re-laparotomy and a measurement of the strength of the anastomosis by decreasing the anastomotic bursting pressure. For this, the anastomotic-bearing part of the colon was removed and into a

Measuring apparatus used. Intraluminal pressure was increased until bursting of the anastomosis. The pressure difference was measured. In addition, tissue samples were taken and histological

Hematoxylin-eosin stains were used to verify wound healing carried out.

Statistical analysis:

The data was calculated and evaluated with Graphpad Prism 7. As a significance test, a Welch-T test was used for two independent samples with unequal standard deviations in both populations. Experimental results:

Seven (7) days after anastomosis, the anastomotic burst pressure reading in the NaCI (0.9%) control group with colonic anastomosis was significantly lower than in the wound healing material group with colonic anastomosis (t = 3, 0, p <0.05). Significant Differences in Wound Healing Improving Material Group with Colon Anastomosing for Wound Healing Improving Material Control Group without Colon Anastomosis (t = 2.5; p> 0.05) or NaCI (0.9%) Control without Colon There was no anastomosis.

The results are shown in Figure 1 and Table 1.

Claims

PlantTec Medical GmbH 1015/001 WO 03.07.2017 jh / do Claims

1.) Medicines, a. ) containing up to carboxy-methylated starch and / or b. ) containing up to consisting of epichlorohydrin modified / r

Strength, for the treatment of anastomoses.

2.) Medicament according to claim 1, characterized in that it is used for the treatment of anastomoses in and / or on the intestine.

3.) Medicament according to claim 1, characterized in that it is used for the treatment of anastomoses of mesenchymal organs.

4.) Medicament according to claim 3, characterized in that it is the bones, tendons, muscles, adipose tissue and connective tissue in the mesenchymal organs.

5.) Medicament according to one of claims 1 to 4, characterized

characterized in that it is used for the treatment of epithelial defects.

6.) Medicament according to one of claims 1 to 5, characterized in that this is used for the treatment of wounds.

7.) Medicaments according to one of claims 1 to 6, characterized

characterized in that it is in gel form.

8.) Medicaments according to one of claims 1 to 7, characterized

characterized in that it contains water and / or at least one salt.

9.) Medicament according to one of claims 1 to 8, characterized

characterized in that the starch has a molecular weight of 500,000 to 11,000,000 daltons and / or the starch has a particle diameter of 30 μηι to 100 μιτι.

10.) A process for the preparation of a medicament according to one of

Claims 1 to 9 by providing the indicated in claim 1 strength.

11.) Use of a medicament according to one of claims 1 to 9 for the treatment of an indication of indicated in claims 1 to 6 Indications.

12.) Use of a. ) carboxy-methylated starch and / or b. ) epichlorohydrin modified starch for the manufacture of a medicament for the treatment of anastomoses.

13.) Use according to claim 12, characterized in that the treatments are those which are indicated in claims 2 to 6. Process for the treatment of anastomoses, characterized in that a medicament according to any one of claims 1 to 9 is used.

A method according to claim 14, characterized in that the drug is applied topically.